Tselios Konstantinos, Sarantopoulos Alexandros, Gkougkourelas Ioannis, Boura Panagiota
Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Greece.
Clin Exp Rheumatol. 2014 Sep-Oct;32(5):630-9. Epub 2014 Sep 8.
Several studies have reported low numbers of T regulatory cells (Tregs) in active systemic lupus erythematosus (SLE). However, it is not evident if these cells may be utilised as a biomarker in assessing disease activity.
Tregs (CD4+CD25highFOXP3+) were prospectively assessed by flow cytometry in 285 separate blood samples from 100 white Caucasian SLE patients and 20 healthy controls. Patients were divided, according to disease activity (as measured by SLEDAI) into groups A (n=39, samples=94, SLEDAI=0), B (n=33, samples=92, SLEDAI=1-5), C (n=10, samples=53, SLEDAI=6-10) and D (n=18, samples=46, SLEDAI>10). Longitudinal measurements were performed in 131 cases (37 relapses, 44 remissions and 50 cases with stable disease activity) during three years. Statistics were performed by Student's t-test or one-way ANOVA; correlations with Pearson co-efficient, while p<0.05 was considered significant.
Tregs were found significantly lower in severely active disease (group D), compared to healthy controls, inactive disease, mild and moderate disease activity (0.57±0.16% vs. 1.49±0.19%, 1.19±0.34% and 1.05±0.36%, 0.72±0.21%, p<0.05, respectively). There was a strongly inverse correlation between Tregs and SLEDAI (r=-0.644, p<0.001). Alterations in disease activity were characterised by inverse alterations in Tregs: relapse (from 1.23±0.44% to 0.64±0.19%, p<0.001, mean change 0.59±0.41%), remission (from 0.65±0.27% to 1.17±0.30%, p<0.001, mean change 0.52±0.35%). In cases with unaltered disease activity, Treg numbers remained stable (from 0.98±0.35% to 1.03±0.34%, p=0.245). Tregs were practically halved during relapse (mean reduction 42.6±22.2%), and doubled during remission (mean increment 113±120.9%). Mean change of Tregs in stable disease was significantly lower (7.3±20.6%, p<0.001). A clinically significant change in SLEDAI (sum of cases with relapse and remission, n=81) was followed by a significant (>20%) inverse change in Tregs in 71/81 cases (sensitivity 87.7%). In 50 cases of stable disease activity, Tregs were significantly changed (>20%) in 13 cases (specificity 74%). Positive predictive value (PPV) was 84.5% and negative predictive value (NPV) was 78.7%.
CD4+CD25highFOXP3+ T regulatory cells displayed a strongly inverse correlation to disease activity in the long term. Treg alterations reflected changes in SLEDAI with high sensitivity. These cells may be a reliable biomarker for the assessment of disease activity in SLE by longitudinal measurements.
多项研究报告称，活动性系统性红斑狼疮（SLE）患者体内的调节性T细胞（Tregs）数量较少。然而，这些细胞是否可用作评估疾病活动的生物标志物尚不清楚。
通过流式细胞术对100名白种人SLE患者和20名健康对照者的285份独立血样中的Tregs（CD4+CD25highFOXP3+）进行前瞻性评估。根据疾病活动度（用SLEDAI衡量）将患者分为A组（n=39，样本=94，SLEDAI=0）、B组（n=33，样本=92，SLEDAI=1-5）、C组（n=10，样本=53，SLEDAI=6-10）和D组（n=18，样本=46，SLEDAI>10）。对131例患者在三年期间进行了纵向测量（37例复发、44例缓解和50例疾病活动稳定）。采用学生t检验或单因素方差分析进行统计学分析；采用Pearson相关系数进行相关性分析，p<0.05被认为具有统计学意义。
与健康对照、非活动性疾病、轻度和中度疾病活动相比，严重活动性疾病（D组）中的Tregs显著降低（0.57±0.16% 对 1.49±0.19%、1.19±0.34%、1.05±0.36%、0.72±0.21%，p<0.05）。Tregs与SLEDAI之间存在强烈的负相关（r=-0.644，p<0.001）。疾病活动度的改变以Tregs的反向改变为特征：复发（从1.23±0.44%降至0.64±0.19%，p<0.001，平均变化0.59±0.41%）、缓解（从0.65±0.27%升至1.17±0.30%，p<0.001，平均变化0.52±0.35%）。在疾病活动度未改变的病例中，Treg数量保持稳定（从0.98±0.35%至1.03±0.34%，p=0.245）。复发期间Tregs几乎减半（平均减少42.6±22.2%），缓解期间翻倍（平均增加113±120.9%）。稳定疾病中Tregs的平均变化显著更低（7.3±20.6%，p<0.001）。SLEDAI出现具有临床意义的变化（复发和缓解病例总数，n=81）后，71/81例患者的Tregs出现显著的反向变化（>20%）（敏感性87.7%）。在50例疾病活动稳定的病例中，13例患者的Tregs出现显著变化（>20%）（特异性74%）。阳性预测值（PPV）为84.5%，阴性预测值（NPV）为78.7%。
长期来看，CD4+CD25highFOXP3+调节性T细胞与疾病活动度呈强烈负相关。Treg改变以高敏感性反映了SLEDAI的变化。通过纵向测量，这些细胞可能是评估SLE疾病活动度的可靠生物标志物。
